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Journal articles on the topic 'ICOLL response'
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Solinas, Cinzia, Chunyan Gu-Trantien, and Karen Willard-Gallo. "The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy." ESMO Open 5, no. 1 (January 2020): e000544. http://dx.doi.org/10.1136/esmoopen-2019-000544.
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Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.
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Wang, Bin, Huayong Jiang, Tingyang Zhou, Ning Ma, Wei Liu, Yajie Wang, and Li Zuo. "Expression of ICOSL is associated with decreased survival in invasive breast cancer." PeerJ 7 (May 16, 2019): e6903. http://dx.doi.org/10.7717/peerj.6903.
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Background Inducible co-stimulator (ICOS) is a CD28-related molecule exclusively expressed on activated T cells and plays a critical role in modulating the immune response in breast cancer. The blockage of ICOS pathway has been shown to inhibit the activity of Type 2 T helper cells, thus potentially protecting against cancer growth. The current study aims to investigate the correlation between inducible co-stimulator ligand (ICOSL) expression in tumor tissues and the prognoses of patients with invasive breast cancer. Methods Tumor samples from 562 Chinese patients with invasive breast carcinomas were collected between 2003 and 2010. The expression of ICOSL on breast tumor and adjacent non-cancerous tissue was determined via immunohistochemistry. The overall survival (OS) of patients with positive and negative ICOSL expression were described using Kaplan–Meier curves, respectively. Parametric correlation method was used to analyze the correlation between ICOSL expression and other clinicopathological parameters. ICOSL was selected as a dependent variable for multivariate analysis. Results Positive ICOSL expression was identified on the plasma membrane in both cytoplasm and the nucleus of breast cancer cells. Membrane-expressed ICOSL is determined as an independent prognostic factor for OS in breast cancer but without significantly correlating with other clinicopathologic parameters such as age, menopausal status, depth of invasion, lymph node metastasis status, histologic classification, etc. Conclusion Our study suggests that the up-regulated expression of ICOSL protein in breast tumor cells can be associated with poor prognoses in invasive breast carcinomas.
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Mali, Yustinus Calvin Gai. "EFL STUDENTS’ EXPERIENCES IN LEARNING CALL THROUGH PROJECT BASED INSTRUCTIONS." TEFLIN Journal - A publication on the teaching and learning of English 28, no. 2 (July 9, 2017): 170. http://dx.doi.org/10.15639/teflinjournal.v28i2/170-192.
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Various initiatives led by Ministries of Education and related entities in many countries around the world have encouraged teachers not only to integrate technology in their teaching practices but also to employ various sound teaching methods that allow learners to be actively involved in the teaching and learning process. As a response to these issues, this qualitative study delves closely into students’ perspectives on the implementation of Project Based Learning (PBL) activities in an Introduction to Computer Assisted Language Learning (ICALL) course. Thirty students participated in the study by submitting reflective notes that answer four questions concerning the implementation of PBL in the course. Approached through the lens of content analysis paradigms, the data analysis results showed the students’ positive responses to the employment of PBL in exploring potential technology for language teaching and learning purposes. Implications for ICALL course designs particularly in English as a Foreign Language (EFL) higher education context and directions for further research were also discussed.
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Ayunon, Chirbet Cariño, and Lysel Ildefonso Haloc. "How far have we gone? Integration of intercultural language learning principles in Philippine ESL classrooms." Journal of Education and Learning (EduLearn) 15, no. 1 (February 1, 2021): 144–52. http://dx.doi.org/10.11591/edulearn.v15i1.20056.
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Intercultural education is firmly rooted on the notion that language and culture are intrinsically linked. Several studies have looked into the importance of understanding different languages and cultures in language teaching; however, studies on the integration of principles intercultural language learning (IcLL) in Philippine ESL classrooms seem to be lacking. This is what the article addresses as it looked into the extent of integration of IcLL principles in two higher educational institution in Region 2, Cagayan Valley, Northern Philippines. Anchored on the principles of IcLL and through the employment of survey to elicit responses of the language teachers as to the integration of IcLL principles in language classrooms, results revealed that teachers perceive IcLL to be integrated in their classrooms to a great extent. Specifically, the principles of active construction and social interaction are integrated to a very high extent while the principles making connections, reflection, and responsibility were perceived to be integrated to a high extent. As regards classroom activities, the teachers favored the employment of discussions, lectures, writing tasks, oral reports, role plays, small group tasks, simulations or skits and collaborative learning activities in transmitting the target culture.
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Yoo, Jae-Kwang, Eleanor N. Fish, and Thomas J. Braciale. "LAPCs promote follicular helper T cell differentiation of Ag-primed CD4+ T cells during respiratory virus infection." Journal of Experimental Medicine 209, no. 10 (September 17, 2012): 1853–67. http://dx.doi.org/10.1084/jem.20112256.
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The humoral immune response to most respiratory virus infections plays a prominent role in virus clearance and is essential for resistance to reinfection. T follicular helper (Tfh) cells are believed to support the development both of a potent primary antibody response and of the germinal center response critical for memory B cell development. Using a model of primary murine influenza A virus (IAV) infection, we demonstrate that a novel late activator antigen-presenting cell (LAPC) promotes the Tfh response in the draining lymph nodes (dLNs) of the IAV-infected lungs. LAPCs migrate from the infected lungs to the dLN “late,” i.e., 6 d after infection, which is concomitant with Tfh differentiation. LAPC migration is CXCR3-dependent, and LAPC triggering of Tfh cell development requires ICOS–ICOSL–dependent signaling. LAPCs appear to play a pivotal role in driving Tfh differentiation of Ag-primed CD4+ T cells and antiviral antibody responses.
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Abolhassani, Hassan, Yasser M. El-Sherbiny, Gururaj Arumugakani, Clive Carter, Stephen Richards, Dylan Lawless, Philip Wood, et al. "Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency." Journal of Clinical Immunology 40, no. 2 (December 20, 2019): 277–88. http://dx.doi.org/10.1007/s10875-019-00735-z.
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Abstract Background Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.
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Ai, Haiyang. "Providing graduated corrective feedback in an intelligent computer-assisted language learning environment." ReCALL 29, no. 3 (May 24, 2017): 313–34. http://dx.doi.org/10.1017/s095834401700012x.
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AbstractCorrective feedback (CF), a response to linguistic errors made by second language (L2) learners, has received extensive scholarly attention in second language acquisition. While much of the previous research in the field has focused on whether CF facilitates or impedes L2 development, few studies have examined the efficacy of gradually modifying the explicitness or specificity of CF as a function of a learner’s response to the feedback. Yet, the type and extent of CF needed by a learner, as suggested by Vygotsky (1978), sheds light on whether a learner is developing his or her abilities in a particular area and the ways in which they do it. This paper reports on a study that explores the design, effectiveness and learners’ perception toward agraduated(Aljaafreh & Lantolf, 1994) approach to CF, i.e., feedback that progresses from very general and implicit to very specific and explicit, in an intelligent computer-assisted language learning (ICALL) environment. The results show that the graduated approach to CF is effective in helping learners to self-identify and self-correct a number of grammatical issues, although an onsite tutor provides necessary remedies when the ICALL system occasionally fails to do its part. Implications for CF research, particularly on the notion of individualized feedback, are also discussed.
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Garofalo, Mariangela, Laura Bertinato, Monika Staniszewska, Magdalena Wieczorek, Stefano Salmaso, Silke Schrom, Beate Rinner, Katarzyna Wanda Pancer, and Lukasz Kuryk. "Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model." Pharmaceutics 13, no. 4 (April 14, 2021): 547. http://dx.doi.org/10.3390/pharmaceutics13040547.
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Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.
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Adom, Djamilatou, Abdulraouf Ramadan, Kushi Kushekhar, and Sophie Paczesny. "ICOSL+ Plasmacytoid Dendritic Cells As Biomarker and Inducer of Graft-Versus-Host Disease." Blood 132, Supplement 1 (November 29, 2018): 355. http://dx.doi.org/10.1182/blood-2018-99-116417.
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Abstract Acute graft-versus-host disease (GVHD) remains one of the leading causes of death post allogeneic hematopoietic cell transplantation (HCT). Gastrointestinal GVHD (GI-GVHD), the most fatal type of GVHD, would benefit from additional biomarkers that are therapeutic targets. Using state-of-the-art quantitative proteomics we previously identified and validated an increased CD4+CD146+ T cell population in GI-GVHD patients. This population expressed a Th1 and Th17 phenotype and was induced by Inducible COStimulator (ICOS), a critical costimulatory molecule for the development of pathogenic Th17 (Li W. et al, J. Clin. Invest. Insights, 2016). ICOS binds its ligand, ICOSL, which is expressed on dendritic cells (DCs) that prime naïve T cells to initiate immune responses. This prompted us to examine ICOSL expression on the two blood DCs subsets that can be identified in human peripheral blood: Lineage-HLADR+CD11c+ myeloid DCs (mDCs) and Lineage-HLADR+CD123+ plasmacytoid DCs (pDCs). Using the same cohort of patients aforementioned, the frequency of ICOSL was significantly higher on pDCs in 64 GI-GVHD patients when compared to 22 non-GVHD enteritis patients, 35 skin GVHD patients, and 39 patients without GVHD (Figure 1). The numbers and frequencies of total DCs, mDCs and pDCs were similar between groups. The growth factor fms-related tyrosine kinase 3 ligand (Flt3l) is necessary for the development and differentiation of pDCs, and the transcription factor, Stat3, is required for Flt3l-dependent dendritic cell differentiation in mice. The role of pDCs in acute GVHD is still controversial (tolerogenic or initiator of GVHD depending on the murine model), and confirmatory studies about their functions are necessary before a therapeutic approach based on this mechanism can be contemplated. Based on the patients' data and previous knowledge, we hypothesized that absence of ICOSL signaling in donor DCs would protect against GVHD through Flt3l, Stat3, or both. We first found that knocking out (KO) ICOSL in the donor bone marrow (BM) extended survival compared to wild-type (WT) mice in the major mismatch (B6, H-2b à BALB/c, H-2d) experimental HCT model, while recipients of Stat3KO BM did not show any difference in GVHD mortality (Figure 2A). We also found a significant decrease of Flt3l levels in plasma collected at day 3 from ICOSLKO BM recipients compared to WT mice (Figure 2B). We then analyzed the recipients' infiltrating intestinal immune cells at day 10 post-HCT for the infiltration of pDCs and pathogenic Th17 cells. We found significantly lower frequencies of intestinal pDCs (CD11b-CD11c+B220+CD103+) (Figure 2C), and intestinal T cells coexpressing interferon (IFN)g and IL-17 (Figure 2D) in recipients of ICOSLKO BM compared to recipients of WT BM. Absolute counts of these two populations followed the same trend (data not shown). To confirm these data were not strain-specific, we performed similar analyses in the haplo-identical (B6, H-2b à B6D2F1, H-2d) experimental model showing similar outcomes for pDCs and IFNγ+IL-17+ T cells frequencies and counts in recipients of ICOSLKO BM compared to recipients of WT BM. Importantly, and in contrast to human T cells, CD146 is not expressed on naïve murine T cells and thus cannot be measured in vivo in acute GVHD models. Transcriptome analyses by Nanostring technology (Immunology panels) comparing 14 days post-HCT of sorted pDCs from ICOSLKO BM versus WT haplo-identical recipients showed increased expression of key molecules required for development (Itgax, Nos2, Socs1, Tcf4 and Bst2), costimulation (Cd80, Cd48, Cd74 and Cd86), and function (Tyrobp, Ikbkg, Nod2 and Irf7) of pDCs (Figure 3A). Lastly, we found increased T cell activation markers including Prf1, Il17a, eomes in sorted CD4+ T cells from ICOSLKO BM compared to WT recipients (Figure 3B). We conclude that early quantification of ICOSL+ pDCs frequency may allow identification of patients at risk of GI-GVHD development. Targeting ICOSL may represent a new avenue to treat acute GVHD. Disclosures Paczesny: Viracor IBT Laboratories: Patents & Royalties.
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Peng, Baowei, Peiqing Ye, Bruce R. Blazar, Gordon J. Freeman, David J. Rawlings, Hans D. Ochs, and Carol H. Miao. "Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice." Blood 112, no. 5 (September 1, 2008): 1662–72. http://dx.doi.org/10.1182/blood-2008-01-128413.
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Abstract Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid–treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS+CD4+ T cells and activation of CD25+Foxp3+ Tregs in the peripheral blood, spleen, and lymph nodes. CD4+ T cells from anti-ICOS–treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-β. Moreover, CD4+CD25+ Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS–treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Φx 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.
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Carrell, Rebecca K., Rebecca A. Stanton, Stephen P. Ethier, Amanda C. LaRue, and Adam C. Soloff. "ICOSL-augmented adenoviral-based vaccination induces a bipolar Th17/Th1 T cell response against unglycosylated MUC1 antigen." Vaccine 36, no. 42 (October 2018): 6262–69. http://dx.doi.org/10.1016/j.vaccine.2018.09.010.
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Fu, Tihui, Qiuming He, and Padmanee Sharma. "The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy." Cancer Research 71, no. 16 (June 27, 2011): 5445–54. http://dx.doi.org/10.1158/0008-5472.can-11-1138.
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Hoffmann, Caroline, Aurore Surun, Floriane Noel, Paula Michea, Maximilien Grandclaudon, Lilith Faucheux, Philemon Sirven, et al. "Use of PD-L1 and ICOSL to discriminate innate and adaptive dendritic cells in the head and neck cancer microenvironment." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14184-e14184. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14184.
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e14184 Background: Inflamed head and neck squamous cell carcinomas (HNSCC), have a better prognosis independently of the treatment modalities, and have an increased response rate to PD(L)1 blockade. Dendritic cells (DC) infiltration is associated to T cell infiltration and DC are critical in the immune response to cancer, but little is known on HNSCC infiltrating DC. The objectives were to determine the differences between DC infiltrating inflamed vs non inflamed tumors, to understand which mechanisms modulate DC phenotypes and which are the associated functions. Methods: 22 untreated HNSCC were characterized by flow cytometry for their immune infiltrate. RNA sequencing of sorted tumor infiltrating myeloid subsets and blood DC were analyzed for differentially expressed genes. The TMod database (Grandclaudon et al.), testing the effect of various stimuli on DC and subsequently on co-cultured T cells, was used to decipher DC and T cell modulation. Results: The level of CD3 infiltration was positively associated to the level of DC infiltration and PDL1 expression on myeloid cells, and negatively to the level neutrophils and of ICOSL expression on myeloid cells. PDL1high ICOSLneg DC from inflamed tumors were matched with the “innate DC” phenotype described in vitro, highly efficient at secreting cytokines and chemokines but poorly activating naïve CD4 T cells. DC from non-inflamed tumor resembled immature medium DC. A third type of DC, “adaptive DC”, expressing high levels of ICOSL and low of PDL1, poorly efficient at cytokine and chemokine secretion, but highly efficient at activating T cells is was described in vitro, but not found in tumors. RNAseq analysis confirmed this innate polarization and highlighted that those cells present a mature and NFkB activated phenotype. Conclusions: Inflamed HNSCC contain stimuli able to induce the recruitment and the differentiation of DC into mature, NFkB activated “innate” DC, highly efficient at secreting cytokines and chemokines but poorly activating naïve CD4 T cells. These data partly explain the superiority of CPS over TPS for the prediction of response to PD(L)1 blockade. More importantly, the stimuli identified here may be used as adjuvants to induce this DC « innate » maturation in non-inflamed tumors, but should only be used in combination with anti-PD(L)1 immunotherapy.
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Balasubramanian, Bharathi, Ted Lis, Zhenhua Wu, Cheryl Gretzula, Irene Gregan, Vic Uebele, Steve Fox, Armando Lagrutta, John Imredy, and Frederick Sannajust. "Responses of iCell hIPSC-derived cardiomyocytes to cardiac modulators in the xCELLigence cardio label free impedance platform." Journal of Pharmacological and Toxicological Methods 70, no. 3 (November 2014): 355. http://dx.doi.org/10.1016/j.vascn.2014.03.157.
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Shen, C., C. Hupin, A. Froidure, B. Detry, and C. Pilette. "Impaired ICOSL in human myeloid dendritic cells promotes Th2 responses in patients with allergic rhinitis and asthma." Clinical & Experimental Allergy 44, no. 6 (May 24, 2014): 831–41. http://dx.doi.org/10.1111/cea.12308.
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Mao, Yong, Cheng Wang, Fanyi Meng, Jiehong Kong, Suping Cao, Yiguo Jiang, Weipeng Wang, and Dong Hua. "Polymorphisms in the ICOS/CD28-ICOSL pathway are related to capecitabine-based chemotherapy response in advanced colon cancer patients." Molecular Immunology 96 (April 2018): 78–82. http://dx.doi.org/10.1016/j.molimm.2018.02.017.
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Hausl, Christina, Rafi U. Ahmad, Hans Peter Schwarz, Eva M. Muchitsch, Peter L. Turecek, Friedrich Dorner, and Birgit M. Reipert. "Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders." Blood 104, no. 1 (July 1, 2004): 115–22. http://dx.doi.org/10.1182/blood-2003-07-2456.
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Abstract Memory B cells are responsible for the rapidly emerging antibody response after antigen reexposure. The signals required for the restimulation of memory B cells have not been fully explained. We used a murine model of anti–factor VIII (FVIII) antibody responses in hemophilia A to study the requirements for the restimulation of FVIII-specific memory B cells and their differentiation into anti-FVIII antibody-producing cells. We were particularly interested in the significance of activated T cells and costimulatory interactions. Our results indicate that the restimulation of FVIII-specific memory B cells is strictly dependent on interactions with activated T cells. These activated T cells can be specific for either FVIII or third-party antigens. Restimulation by T cells specific for third-party antigens requires the presence of FVIII, indicating that signals induced by B-cell receptor (BCR) triggering and by interactions with activated T cells are important. The blockade of B7-1 or B7-2 as well as the blockade of CD40L inhibits the restimulation and differentiation of FVIII-specific memory B cells in vitro and in vivo. The interference with inducible costimulator–inducible costimulator ligand (ICOS-ICOSL) interactions, however, does not cause any modulation. As expected, the production of anti-FVIII antibodies by plasma cells is not dependent on any of the costimulatory interactions tested.
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Daneshmandi, Saeed, Ali Akbar Pourfathollah, and Mehdi Forouzandeh-Moghaddam. "Enhanced CD40 and ICOSL expression on dendritic cells surface improve anti-tumor immune responses; effectiveness of mRNA/chitosan nanoparticles." Immunopharmacology and Immunotoxicology 40, no. 5 (September 3, 2018): 375–86. http://dx.doi.org/10.1080/08923973.2018.1510959.
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Maurer, Deena M., Juraj Adamik, Patricia M. Santos, Jian Shi, Michael R. Shurin, John M. Kirkwood, Walter J. Storkus, and Lisa H. Butterfield. "Dysregulated NF-κB–Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma." Cancer Immunology Research 8, no. 12 (October 13, 2020): 1554–67. http://dx.doi.org/10.1158/2326-6066.cir-20-0274.
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Στρίγκας, Κωνσταντίνος Πέτρος, Αλκιβιάδης Τσιμπίρης, and Δημήτριος Βαρσάμης. "Εξ Αποστάσεως Επιμόρφωση Εκπαιδευτικών από το 4ο ΠΕ.Κ.Ε.Σ. Κ. Μακεδονίας. Εφαρμογή, αποτίμηση και προοπτική. Teacher Training with Distance e-Learning. Application, Valuation and Perspective." Διεθνές Συνέδριο για την Ανοικτή & εξ Αποστάσεως Εκπαίδευση 10, no. 1B (February 10, 2020): 108. http://dx.doi.org/10.12681/icodl.2336.
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Σκοπός της εργασίας είναι η διερεύνηση της επίδρασης της εξ αποστάσεως εκπαίδευσης στη διαδικασία επιμόρφωσης των εν ενεργεία Εκπαιδευτικών Πρωτοβάθμιας και Δευτεροβάθμιας Εκπαίδευσης. Έγινε καταγραφή των απόψεων μετά από τη συμμετοχή τους σε προγράμματα εξ αποστάσεως επιμόρφωσης. Το 4ο Περιφερειακό Κέντρο Εκπαιδευτικού Σχεδιασμού (ΠΕΚΕΣ) Κ. Μακεδονίας σε συνεργασία με το «itlab» εργαστήρι πληροφορικής του Διεθνούς Πανεπιστημίου Ελλάδος (ΔΙ.ΠΑ.Ε.) ανταποκρινόμενο στις απαιτήσεις των εκπαιδευτικών για συνέχιση των εξ αποστάσεως επιμορφωτικών προγραμμάτων του σχολικού έτους 2017-2018 υλοποίησε τέσσερα (4) προγράμματα εξ αποστάσεως επιμόρφωσης, με χρήση της πλατφόρμας ασύγχρονης εκπαίδευσης OpeneClass και της πλατφόρμας σύγχρονης εκπαίδευσης BigBlueButton. Με την ολοκλήρωση σε καθένα από τα προγράμματα υλοποιήθηκε έρευνα με ερωτηματολόγια ερωτήσεων κλειστού και ανοικτού τύπου μέσω της πλατφόρμας, ώστε να καταγραφούν οι στάσεις, οι απόψεις και οι προτάσεις των εκπαιδευτικών για την εμπειρία τους κατά την διάρκεια της τηλεπιμόρφωσης καθώς και τα συμπεράσματά τους για την υλοποίηση εξ αποστάσεως επιμορφώσεων γενικότερα. Έγινε αποτίμηση και επισκόπηση των απαιτούμενων εκπαιδευτικών πόρων στην εφαρμογή εξ αποστάσεως εκπαίδευσης. The aim of this program is to investigate the impact of distance learning on teachers training processes of education of primary and secondary teachers in active education. Τhe opinions of the Teachers were recorded, after their attendance of distance learning courses. The 4th PEKES of Central Macedonia in collaboration with the ITlab Computer Lab of the International Hellenic University in response to the demands of teachers for the continuation distance learning programs of last scholar year (2017-2018) realized four distance learning programs. The courses were developed on the OpeneClass asynchronous training platform, supported by the synchronous BigBlueButton training platform. Α questionnaire of closed-ended questions was answered through the platform in order to capture the opinions of the teachers for their experience of the online training. The required educational resources in distance learning implementation were evaluated and reviewed.
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Abuqayyas, L., L. Cheng, D. Mitragotri, S. Smith, M. Teixeira Dos Santos, Y. Zhou, V. Chindalore, et al. "FRI0084 SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS, IMMUNOGENICITY, AND PRELIMINARY EFFICACY OF ROZIBAFUSP ALFA IN SUBJECTS WITH RHEUMATOID ARTHRITIS: INTERIM ANALYSIS OF A PHASE 1B RANDOMIZED, PLACEBO-CONTROLLED, MULTIPLE ASCENDING DOSE CLINICAL TRIAL." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 619–20. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4744.
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Background:Autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are associated with autoantibody production and dysregulated T- and B-cell responses. Rozibafusp alfa (AMG 570) is a first-in-class bispecific antibody-peptide conjugate targeting T- and B-cell activity through inhibition of ICOSL and BAFF and is currently in phase 2 clinical development for the treatment of SLE.Objectives:This interim analysis of a phase 1b study (NCT03156023) reports the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy of rozibafusp alfa in subjects with RA.Methods:Subjects (N~34; age 18–75 years) with active RA, defined as a disease activity score (DAS28-CRP) >2.6, were randomized 3:1 to receive rozibafusp alfa or placebo subcutaneously every 2 weeks for 10 weeks (6 doses), with 24 weeks of follow-up. Subjects were divided into 4 cohorts to study 4 ascending doses of rozibafusp alfa. All subjects were maintained on a stable dose of methotrexate. The primary endpoint was the subject incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum PK profiles, PD (eg, ICOSL receptor occupancy [RO], changes in peripheral blood B cells), incidence of anti-rozibafusp alfa antibodies, and Patient and Physician Global Assessments (PtGA and PhGA) of disease activity.Results:As of June 5, 2019, 34 subjects were enrolled and included in this interim analysis. Rozibafusp alfa was generally well tolerated. TEAEs occurred in 92.3% and 87.5% of subjects receiving rozibafusp alfa and placebo, respectively. Most of these events were of grade ≤2 severity. The most common TEAE was upper respiratory infection (23.1%) for subjects receiving rozibafusp alfa and nasopharyngitis (37.5%) for subjects receiving placebo. No treatment-related AEs were of grade ≥3 severity and occurred in >2 subjects. Rozibafusp alfa demonstrated a nonlinear PK profile with greater than a dose-proportional increase in concentration across evaluated doses. The terminal half-life of rozibafusp alfa ranged from 5 to 11 days, with longer half-lives at higher dose levels. ICOSL RO on circulating B-cells was dose-related and reversible; upon multiple dosing, >90% mean RO was observed in cohorts 3 and 4. Treatment with rozibafusp alfa reduced the percentage of naïve B-cells and increased the percentage of memory B-cells in all cohorts. As of March 22, 2019, 2 of 18 (11.1%) rozibafusp alfa-treated subjects developed anti-rozibafusp alfa antibodies with no correlation to safety or AEs. Preliminary analysis of disease-related activity showed a trend for greater numerical improvement from baseline in PtGA and PhGA with rozibafusp alfa vs. placebo in cohorts 3 and 4.Conclusion:This interim analysis is the first to report the safety and tolerability of multiple ascending doses of rozibafusp alfa in RA subjects, with preliminary efficacy findings observed in the highest dose cohorts. PK/PD analysis demonstrated nonlinear, target-mediated disposition consistent with cell surface target interaction and PD activity consistent with dual ICOSL/BAFF neutralization. These findings informed the design and dose selection of an ongoing phase 2, randomized, placebo-controlled study to assess the efficacy and safety of rozibafusp alfa in subjects with active SLE and inadequate responses to standard of care therapy.Acknowledgments:Amgen Inc. and AstraZeneca sponsored this phase 1b studyDisclosure of Interests:Lubna Abuqayyas Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Laurence Cheng Shareholder of: Stockholder of Amgen Inc., Employee of: Former employee of Amgen Inc., Deepali Mitragotri Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Shawna Smith Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Marcia Teixeira dos Santos Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Yanchen Zhou Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Vishala Chindalore Grant/research support from: Nektar Therapeutics for conducted studies, Speakers bureau: > 5 years ago, Stanley Cohen Grant/research support from: Grant and research support from Amgen, AbbVie, Pfizer, Genentech, and Lilly, Consultant of: Consultant for Amgen, AbbVie, Pfizer, Genentech and Lilly, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Maximilian Posch: None declared, Barbara Sullivan Shareholder of: Shareholder of Amgen Inc., Employee of: Former employee of Amgen Inc. Current employee of Ultragenyx, Jane Parnes Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc.
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Yang, Jing, Jan L. Hillson, Kristi L. Manjarrez, Jennifer R. Wiley, Gary D. Means, Stacey R. Dillon, and Stanford L. Peng. "An Open Label Study of Alpn-101, a First-in-Class Dual CD28/ICOS Antagonist, in Subjects with Steroid-Resistant or Steroid-Refractory Acute Graft Versus Host Disease (aGVHD)." Blood 134, Supplement_1 (November 13, 2019): 372. http://dx.doi.org/10.1182/blood-2019-126034.
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Background: Cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) provide costimulatory signals required for optimal T cell activation when bound to their respective ligands, CD80 (B7-1) and CD86 (B7-2), and ICOS ligand (ICOSL). CD28 is involved in initiation of the pathogenic process in GVHD and recent studies suggest therapeutic utility of CD28 pathway inhibitors for prophylaxis and treatment. However, CD28 pathway inhibition alone appears insufficient to control established disease in most patients. In this context, it is recognized that following initial activation, CD28 is often down-regulated while ICOS, its most closely related family member, is upregulated, providing additional T cell costimulation that may sustain GVHD including gastrointestinal manifestations (Adom D et al. Blood. 2018; 132:355). In murine models of aGVHD, combined blockade of CD28 and ICOS was significantly superior to isolated blockade of the CD28 or ICOS pathways alone. ALPN-101 is an Fc fusion protein of a human ICOSL variant immunoglobulin domain (vIgDTM) designed to inhibit both the CD28 and ICOS costimulatory pathways. Nonclinical studies of ALPN-101 demonstrate high affinity binding to CD28 and ICOS, potent inhibition of T cell activation, and suppression of disease activity in a human xenogeneic model of GVHD in mice, after only a single dose (Dillon SR et al. Blood. 2018; 132:2037). ALPN-101 is in development as a novel and potentially transformative approach for GVHD. A first-in-human study of ALPN-101 in healthy subjects is ongoing. This clinical study will assess the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in subjects with aGVHD. Study Design and Methods: Adults with Grade II-IV aGVHD per Mount Sinai Acute GVHD international Consortium (MAGIC) criteria (Harris et al. 2016) that is resistant or refractory to glucocorticoids will receive a single intravenous dose of ALPN-101. This study will be conducted in two parts including dose escalation and dose expansion. Dose escalation will proceed by using an accelerated titration design. Thereafter, a selected dose level(s) will be evaluated in an expansion cohort of 10 subjects; if ≥ 25% (n=3) subjects achieve response, 15 additional subjects will be enrolled (Simon two-stage design). Background Therapy:At the investigator's discretion, subjects may continue therapies administered for prophylaxis, continue or increase glucocorticoids, and/or add another salvage therapy. Responders will be considered for glucocorticoid taper. Endpoints: Safety will be assessed based on the incidence, severity, and seriousness of adverse events. Efficacy endpoints include the objective response rate, duration of response, failure-free survival, event-free survival, non-relapse mortality, malignancy relapse/progression, overall survival, and glucocorticoid use. The incidence and titer of anti-drug antibodies will be assessed. Serum concentrations of ALPN-101 will be measured and PK parameters will be estimated. PD endpoints include target saturation and immunophenotyping of circulating leucocytes, and may include quantification of circulating cytokines, immunoglobulins, acute phase reactants, and soluble forms of the targeted pathway receptor, evaluation of changes in mRNA expression in circulating leucocytes, evaluation of risk alleles, and correlates of response. Disclosures Yang: Alpine immune sciences: Employment, Equity Ownership. Hillson:Alpine Immune Sciences: Employment, Equity Ownership. Manjarrez:Alpine Immune Sciences: Employment, Equity Ownership. Wiley:Alpine Immune Sciences: Employment, Equity Ownership. Means:Alpine Immune Sciences: Employment, Equity Ownership. Dillon:Alpine Immune Sciences: Employment, Equity Ownership. Peng:Alpine Immune Sciences: Employment, Equity Ownership.
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Sullivan, B. A., W. Tsuji, A. Kivitz, J. Peng, G. E. Arnold, M. J. Boedigheimer, K. Chiu, et al. "Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus." Lupus Science & Medicine 3, no. 1 (April 2016): e000146. http://dx.doi.org/10.1136/lupus-2016-000146.
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Wiesemann, Elke, Milani Deb, Corinna Trebst, Bernhard Hemmer, Martin Stangel, and Anja Windhagen. "Effects of interferon-β on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-β treatment in patients with multiple sclerosis." Multiple Sclerosis Journal 14, no. 2 (October 17, 2007): 166–76. http://dx.doi.org/10.1177/1352458507081342.
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Interferon-beta (IFN-β) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-β is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-β on the expression of co-signaling pathways (CD28—CD80/CD86, CD154—CD40, ICOS—ICOSL, PD-1—PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-β in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-β, and in vivo in whole blood samples of 32 untreated and 24 IFN-β treated MS patients, including 13 patients longitudinal. IFN-β treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-β treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-β ( P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-β upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-β in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-β treatment at early timepoints during IFN-β therapy. Multiple Sclerosis 2008; 14: 166—176. http://msj.sagepub.com
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Michallet, Anne-Sophie, Marie-Sarah Dilhuydy, Fabien Subtil, Valérie Rouille, Beatrice Mahe, Kamel Laribi, Bruno Villemagne, et al. "Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial." Blood 134, Supplement_1 (November 13, 2019): 3038. http://dx.doi.org/10.1182/blood-2019-126720.
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Introduction In previously untreated, medically fit patients with chronic lymphocytic leukaemia (CLL) and no 17p deletion, there is current research interest in improving survival outcomes and potentially sparing some patients from the standard 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). The phase II ICLL-07 (NCT02666898) trial, conducted by the French Innovative Leukemia Organization (FILO), aimed to explore the efficacy of obinutuzumab and ibrutinib treatment induction for 9 months, followed by a minimal residual disease (MRD)-driven strategy. Methods Following assessment at Month 9, patients in complete response (CR) with bone marrow (BM) MRD <0·01% continued only ibrutinib 420 mg po daily for 6 additional months (I arm). Otherwise, patients received 4x4-weekly cycles of fludarabine/cyclophosphamide (FC) and obinutuzumab 1000 mg iv, alongside continuing ibrutinib for 6 additional months (FCGA+I arm). Beyond Month 16, response was clinically assessed every 3 months and MRD in PB until Month 40 and every 6 months during 36 months. MRD assessment was by 8-colour flow cytometry (limit of detection 10-6). The primary objective was to demonstrate a 30% or higher rate of CR with BM MRD <0·01% at Month 16, by intent-to-treat (ITT) analysis. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. ResultsBetween 10/2015 and 05/2017, 135 patients were enrolled. At Month 9, only 8% of patients reached CR with BM MRD <0·01%, and thus, in accordance with the MRD-driven strategy, were included in the I arm and continued only ibrutinib for 6 additional months. Most patients were included in the FCGA+I arm and received 4 cycles of FC and obinutuzumab, alongside continuing ibrutinib for 6 additional months. At Month 16, the ITT rate of CR with BM MRD <0·01% was 62% (84/135; 90% confidence interval [CI] 55−69). Of note, the primary objective was exceeded, and this high ITT rate was achieved with no more than 4 cycles of FC and obinutuzumab. The CR rate was 73% by investigator assessment versus 75% by an independent review committee. The PB and BM MRD <0·01% rate was 79%. The most common haematological adverse event (AE) was thrombocytopenia in 45 (34%) of 133 patients at grade 1−2 in Months 1−9 and in 43 (33%) of 130 patients at grade 1−2 in Months 9−15. The most common non-haematological AE were infusion-related reaction in 83 (62%) patients at grade 1−2 in Months 1−9 and gastrointestinal disorders in 62 (48%) patients at grade 1−2 in Months 9−15. A total of 49 serious AE occurred, most frequently infections (10), cardiac events (8) and haematological events (8). No treatment-related deaths occurred. After a median follow-up of 26.3 months, the 2-year PFS rate was 98% (95% CI 95−100) (Figure 1) and the 2-year OS rate was 97.5% (95% CI 96−100). The longitudinal follow-up of PB MRD in the entire cohort showed durability of a deep response, with a PB MRD <0.01% rate of 96% (n=92 evaluable patients) at Month 22 and 91% (n=85 evaluable patients) at Month 28. According to the treatment arm, in the FCGA+I arm, the PB MRD <0.01% rate was 99% at Month 22 and 93% at Month 28; by contrast, in the I arm, 77% of patients had PB MRD <0.01% at each of Months 22 and 28. The strategy achieved deep and durable molecular remission with a high level of undetectable (UD) PB MRD that was maintained over time, as shown in Figure 2. At Month 28, the rate of UD PB MRD was 83% in the FCGA+I arm versus 54% in the I arm. According to the immunoglobulin heavy gene variable (IGHV) mutational status, the PB MRD ≥0.01% rate at Month 28 was 4% for the mutated group versus 23% for the unmutated group (p=0.075, Fisher test). Conclusion These findings from the ICLL-07 trial demonstrated that, in previously untreated, medically fit patients with CLL and no 17p deletion, treatment induction with obinutuzumab and ibrutinib followed by an MRD-driven strategy yielded a high rate of CR with BM and PB MRD <0.01%, together with prolonged PFS and OS. With longer follow-up, including assessing the evolution of PB MRD, the response is maintained. This strategy could be an option in the first-line setting, although randomised trial evidence is needed. Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Cymbalista:Sunesis: Research Funding; Roche: Research Funding; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Le Garff-Tavernier:Alexion: Consultancy, Honoraria. Letestu:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.
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Zhang, Yi, Jun Li, Ya-Min Zhang, Xiao-Ming Zhang, and Juan Tao. "Effect of TACI Signaling on Humoral Immunity and Autoimmune Diseases." Journal of Immunology Research 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/247426.
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Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) is one of the receptors of B cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL). TACI is a regulator in the immune responses. TACI inhibits B cell expansion and promotes the differentiation and survival of plasma cells. The mechanisms underlying these effects probably involve changed expressions of some crucial molecules, such as B lymphocyte induced maturation protein-1 (Blimp-1) and inducible T-cell costimulator ligand (ICOSL) in B cells and/or plasma cells. However, abnormal TACI signaling may relate to autoimmune disorders. Common variable immune deficiency (CVID) patients with heterozygous mutations inTACIalleles increase susceptibility to autoimmune diseases.Taci−/−mice and BAFF transgenic mice both develop signs of human SLE. These findings that indicate inappropriate levels of TACI signaling may disrupt immune system balance, thereby promoting the development of autoimmune diseases. In this review, we summarize the basic characteristics of the TACI ligands BAFF and APRIL, and detail the research findings on the role of TACI in humoral immunity. We also discuss the possible mechanisms underlying the susceptibility of CVID patients withTACImutations to autoimmune diseases and the role of TACI in the pathogenesis of SLE.
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Yang, J., J. Hillson, J. Lickliter, K. Manjarrez, A. Tercero, J. Wiley, G. Means, R. Sanderson, K. Carley, and S. L. Peng. "SAT0196 A DOUBLE BLIND, PLACEBO CONTROLLED, SINGLE ASCENDING DOSE (SAD) AND MULTIPLE ASCENDING DOSE (MAD) STUDY OF ALPN-101, A FIRST-IN-CLASS DUAL ICOS/CD28 ANTAGONIST, IN HEALTHY VOLUNTEERS (HV)." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1040. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2388.
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Background:ALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD™) designed to inhibit simultaneously the CD28 and ICOS inflammation pathways (1). ALPN-101 is effective in preclinical studies of lupus, arthritis, and Sjögren’s, and shows greater activity than single pathway inhibitors (2,3,4). It is in development for the treatment of multiple rheumatic and other inflammatory diseases.Objectives:To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in HVMethods:This was a first-in-human study of ALPN-101 (NCT03748836). 72 HV were allocated 4:2 to single intravenous (IV) or subcutaneous (SC) doses of ALPN-101: placebo at 0.001 – 10 mg/kg; 24 HV were allocated 6:2 to repeated IV doses of up to 1 mg/kg weekly x 4. Subjects were followed for 28 (SAD) or 49 (MAD) days to assess safety, PK, target saturation (TS) on T cells, circulating cytokines and PD, the latter based on suppression of IgG responses to keyhole limpet hemocyanin (KLH).Results:ALPN-101 was generally well-tolerated, with no treatment related serious adverse events, no cytokine release, no clinical immunogenicity, and no adverse trends in safety laboratories. Overall, adverse events were reported in 74.2% of subjects on ALPN-101 and 66.7% of subjects on placebo. All events were mild or moderate and resolved without sequelae. Dose-dependent increase in ALPN-101 exposure was observed from 0.012 to 10 mg/kg. The estimated t1/2was 2-8.6 days over 0.3 – 10 mg/kg. SC bioavailability was ~60% at 3 mg/kg. Minimal to modest accumulation was observed with repeat IV dosing. The TS at Cmaxincreased with dose between 0.001–0.03 mg/kg; thereafter the duration of high level TS (>95%) increased with dose (Figure 1). The duration of suppression of IgG anti-KLH response paralleled the duration of high level TS (Figure 2).Figure 1.Mean + SD Target Saturation of ALPN-101 on Circulating CD4+T LymphocytesFigure 2.Mean + SD Serum Anti-KLH IgG Change Relative to BaselineConclusion:ALPN-101 was well tolerated when administered as single doses up to 10 mg/kg or as repeated doses of up to 1 mg/kg weekly for 4 weeks, exhibiting dose-dependent PK, TS and PD including the inhibition of antibody responses to KLH immunization. These findings support future studies to evaluate the efficacy of ALPN-101 in multiple rheumatic and other inflammatory diseases.References:[1]Levin SD et al. Frontiers in Immunology 2020; 10:3086[2]Evans L et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 1531[3]Dillon S et al. Arthritis and Rheumatology 2018:70: Supplement: Abstract 136[4]Dillon S et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 2416Disclosure of Interests:Jing Yang Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jan Hillson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jason Lickliter Consultant of: AUD 2500 from QBiotics for participation in an expert review panel for development of their oncology phase 1 trial (in Nov 2015), Kristi Manjarrez Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine immune sciences, Inc., Almudena Tercero Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jennifer Wiley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Gary Means Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Russell Sanderson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Kay Carley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Stanford L. Peng Shareholder of: Alpine Immune Sciences, Inc., Employee of: CMO and President of Alpine Immune Sciences, Inc.
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Ou, Xijun, Shengli Xu, and Kong-Peng Lam. "Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival." Proceedings of the National Academy of Sciences 109, no. 38 (September 4, 2012): 15401–6. http://dx.doi.org/10.1073/pnas.1200386109.
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Mutations in TNFRSF13B, better known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), contribute to common variable immunodeficiency and autoimmunity in humans. How TACI regulates these two opposing conditions is unclear, however. TACI binds the cytokines BAFF and APRIL, and previous studies using gene KO mice indicated that loss of TACI affected only T-cell–independent antibody responses. Here we demonstrate that Taci−/− mice have expanded populations of T follicular helper (Tfh) and germinal center (GC) B cells in their spleens when immunized with T-cell–dependent antigen. The increased numbers of Tfh and GC B cells in Taci−/− mice are largely a result of up-regulation of inducible costimulator (ICOS) ligand on TACI-deficient B cells, given that ablation of one copy of the Icosl allele restores normal levels of Tfh and GC B cells in Taci−/− mice. Interestingly, despite the presence of increased Tfh and antigen-specific B cells, immunized Taci−/− mice demonstrate defective antigen-specific antibody responses resulting from significantly reduced numbers of antibody-secreting cells (ASCs). This effect is attributed to the failure to down-regulate the proapoptotic molecule BIM in Taci−/− plasma cells. Ablation of BIM could rescue ASC formation in Taci−/− mice, suggesting that TACI is more important for the survival of plasma cells than for the differentiation of these cells. Thus, our data reveal dual roles for TACI in B-cell terminal differentiation. On one hand, TACI modulates ICOS ligand expression and thereby limits the size of Tfh and GC B-cell compartments and prevents autoimmunity. On the other hand, it regulates the survival of ASCs and plays an important role in humoral immunity.
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Peng, Baowei, Peiqing Ye, Bruce R. Blazer, Hans D. Ochs, and Carol H. Miao. "Transient Blockade of ICOS Co-Stimulatory Pathways Induces Long-Term Tolerance to Factor VIII Following Nonviral Gene Transfer of Factor VIII Plasmid into Hemophilia A Mice." Blood 108, no. 11 (November 16, 2006): 3283. http://dx.doi.org/10.1182/blood.v108.11.3283.3283.
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Abstract Formation of inhibitory antibodies is a significant problem encountered in the treatment of hemophilia by replacement therapy. Nonviral gene transfer of a factor VIII plasmid into hemophilia mice induced strong humoral responses through predominantly TH2 signals. The plasmid-treated mice produced persistent, high-level inhibitory antibody specifically against FVIII, representing a unique and useful model for testing various immunomodulation strategies. It was previously demonstrated by our group that transient immunosuppression by CTLA4-Ig and anti-CD40L (MR1) can prevent inhibitory antibody formation following nonviral gene transfer of FVIII plasmid into hemophilia A mice. In this study, we tested if blockade of inducible costimulator (ICOS)-ICOS ligand (ICOSL) pathway in combination with or without agents blocking other co-stimulatory pathways can modulate the immune response following gene therapy treatment. Three groups of mice (n=5/group) were subjected to administration of FVIII plasmid via hydrodynamics-based tail-vein injection, and transient immunosuppressive regimens including anti-ICOS (8 treatment in 2 week period), combination of anti-ICOS (same dose) and CTLA4-Ig (2 treatment at day 0 and 2), and combination of anti-ICOS (same dose) and MR1 (5 treatment in 2 week period). 2 mice from anti-ICOS only group, 3 mice from combination treatment of anti-ICOS and CTLA4-Ig group, and 2 mice from combination treatment of anti-ICOS and MR1 group developed inhibitors at 2 weeks post treatment. The rest of the mice did not develop inhibitors. These results imply that neither synergistic nor additional modulation was achieved by combining CTLA4-Ig or MR1 with anti-ICOS compared to anti-ICOS alone. Subsequently a more frequent and longer anti-ICOS treatment (16 treatment in 4 week period) was administered in two separate groups of FVIII plasmid-treated mice (n=5 and 11 per group, respectively). All the treated mice did not produce inhibitory antibodies against FVIII and produced persistent, high-level (100–300 μg/ml) FVIII gene expression for at least 150 days (experimental period). The CD4+ T cells isolated from the spleen of tolerized mice did not proliferate in response to FVIII stimulation in vitro. Furthermore, higher population of CD4+CD25+ regulatory T cells were detected in peripheral blood in the tolerized mice compared to untreated and plasmid-treated mice. Adoptive transfer of CD4+ T cells isolated from tolerized mice is performed to test if these cells can protect the recipient mice from developing inhibitory antibodies against FVIII. Anti-ICOS treatment has the potential for a new immunomodulatory strategy for preventing the formation of inhibitory antibodies against FVIII following gene therapy.
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da Rocha, Andre Monteiro, Jeffery Creech, Ethan Thonn, Sergey Mironov, and Todd J. Herron. "Detection of Drug-Induced Torsades de Pointes Arrhythmia Mechanisms Using hiPSC-CM Syncytial Monolayers in a High-Throughput Screening Voltage Sensitive Dye Assay." Toxicological Sciences 173, no. 2 (November 25, 2019): 402–15. http://dx.doi.org/10.1093/toxsci/kfz235.
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Abstract We validated 3 distinct hiPSC-CM cell lines—each of different purity and a voltage sensitive dye (VSD)-based high-throughput proarrhythmia screening assay as a noncore site in the recently completed CiPA Myocyte Phase II Validation Study. Blinded validation was performed using 12 drugs linked to low, intermediate, or high risk for causing Torsades de Pointes (TdP). Commercially sourced hiPSC-CMs were obtained either from Cellular Dynamics International (CDI, Madison, Wisconsin, iCell Cardiomyoyctes2) or Takara Bio (CLS, Cellartis Cardiomyocytes). A third hiPSC-CM cell line (MCH, Michigan) was generated in house. Each cell type had distinct baseline electrophysiological function (spontaneous beat rate, action potential duration, and conduction velocity) and drug responsiveness. Use of VSD and optical mapping enabled the detection of conduction slowing of sodium channel blockers (quinidine, disopyramide, and mexiletine) and drug-induced TdP-like activation patterns (rotors) for some high- and intermediate-risk compounds. Low-risk compounds did not induce rotors in any cell type tested. These results further validate the utility of hiPSC-CMs for predictive proarrhythmia screening and the utility of VSD technology to detect drug-induced APD prolongation, arrhythmias (rotors), and conduction slowing. Importantly, results indicate that different ratios of cardiomyocytes and noncardiomyocytes have important impact on drug response that may be considered during risk assessment of new drugs. Finally, we present the first blinded CiPA hiPSC-CM validation results to simultaneously detect drug-induced conduction slowing, action potential duration prolongation, action potential triangulation, and drug-induced rotors in a proarrhythmia assay.
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Allison, James. "Cytotoxic T-lymphocyte-associated Protein 4 and Cancer Therapy." Blood 126, no. 23 (December 3, 2015): SCI—7—SCI—7. http://dx.doi.org/10.1182/blood.v126.23.sci-7.sci-7.
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Abstract The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits CD28 mediated costimulation. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. A recent retrospective study of almost 5,000 patients showed an inflection point at about 2.5 years with essentially no deaths of about 20% of patients for 10 years following treatment. The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. We have also shown that CTLA-4 blockade results in a 2-5 fold increase in the frequency of CD4 T cells expression ICOS (inducible costimulator) in both tumor tissues and blood. This population contains that vast majority of tumor antigen specific cells that produce IFNg and TNFa. The appearance of the ICOS+ CD4 cells serves as a pharmacodynamic marker of a biological effect of anti-CTLA-4 activity. Using mouse models, we have shown that the ICOS/ICOSL pathway is critical for optimal anti-tumor activity of anti-CTLA-4. Furthermore, we have shown that agonist stimulation of ICOS coupled with CTLA-4 blockade results in enhanced anti-tumor efficacy in mouse models, suggest that ICOS is a compelling molecule to develop as a target for agonistic targeting of costimulatory checkpoints. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. Our studies indicate that the mechanisms of anti-PD-1 mediated tumor immunity are distinct from those of anti-CTLA-4, at least as for the role of ICOS+ CD4 T cells. These studies and their implications for cancer therapy will be discussed. Disclosures Allison: Jounce Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Licensed patent.; Bristol Meyers-Squibb: Patents & Royalties: Licensed patent owned by the University of California. Previously received royalties.
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Michallet, Anne-Sophie, Marie-Sarah Dilhuydy, Fabien Subtil, Valérie Rouille, Beatrice Mahe, Kamel Laribi, Bruno Villemagne, et al. "High Rate of Complete Response (CR) with Undetectable Bone Marrow Minimal Residual Disease (MRD) after Chemo-Sparing and MRD-Driven Strategy for Untreated Fit CLL Patients: Final Results of the Icll 07 Filo Trial." Blood 132, Supplement 1 (November 29, 2018): 1858. http://dx.doi.org/10.1182/blood-2018-99-111977.
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Abstract Achievement of CR with undetectable minimal residual disease (uMRD) may be associated with a longer survival in CLL, but BCR signaling inhibitors alone seldom allow reaching uMRD. We conducted a multicenter phase II trial aiming at exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy for patients who do not reach CR with uMRD. Previously untreated fit patients with active Binet stage A and B or stage C CLL, no TP53 mutation/deletion, CIRS score < 7 and ECOG 0 or 1 were eligible. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg/d for 9 months. Assessment of response to induction was performed at month 9, including CT-scan, bone marrow (BM) biopsy, peripheral blood (PB) and BM MRD testing. Patients in CR with BM MRD < 0.01% (by 8-color flow cytometry) received ibrutinib alone for 6 additional months whereas all the other patients received 4 courses of fludarabine (F) + cyclophosphamide (C) and obinutuzumab along with continuous ibrutinib until month 16. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at D1 Month 16. The primary endpoint of this study was the rate of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16 and the assumption that at least 30% of patients would achieve this goal at the end of the overall strategy. Between November 2015 and May 2017, 135 patients (89 males/46 females) were enrolled; 7% were Binet stage A, 67% stage B and 26% stage C. Median age was 62 years (range, 35-80). Genetic alterations included 26% del(11q), 19% trisomy 12 and 56% del(13q); 15% had a complex karyotype and 56% patients had unmutated IGHV status. Median Beta 2 microglobulin was 3.6 mg/L (1.5-7.5) and median GFR (Cockroft) was 81 mL/min (42-173). At Month 9, 92% patients had received the 8 planned infusions of obinutuzumab. Ibrutinib dosage was reduced in 4 patients and definitively discontinued in 3 of them (3.9%) due to AE (atrial fibrillation, atrial flutter and neutropenia). Fifty seven percent of the patients presented at least a grade (G) 3 toxicity during the first 9 months of treatment (neutropenia 24%, anemia 6% and thrombocytopenia 31%). One hundred and thirty patients were evaluable for response at M9 and 5 not evaluable (2 deaths: one sudden at M7 and one accidental at M8; one acute coronary syndrome; one listeria meningitidis and one acute pulmonary edema at day 1 cycle 1). In intention to treat (ITT), ORR was 100% with 41% of patients reaching CR (42% for evaluable patients) but only 12% had BM MRD < 0.01%. Therefore 88% of the patients were planned to receive FC and obinutuzumab treatment while continuing ibrutinib. At month 16, 115 patients were evaluable for response. In ITT, the CR rate was 69% (78% for evaluable patients) and 79% of patients had BM MRD < 0.01% (90% of evaluable patients). Overall, 62% patients achieved CR with BM MRD < 0.01% (ITT) and 70% evaluable patients did so. The IGHV mutational status did not impact the quality of response. During the trial second period (M9 to M16), 38% patients presented at least a G3 toxicity: neutropenia 24%, thrombocytopenia 15%, anemia 1.5%, febrile neutropenia 3%, gastrointestinal disorders 9.5% and cardiac events 2.4%. A total of 41 serious AEs were observed throughout the entire treatment duration: 9 cardiac events including 1 atrial flutter and 3 atrial fibrillations, 4 hemorrhagic events, 7 infections, 3 second cancers (2 basocellular carcinoma, 1 renal adenocarcinoma) and 2 deaths. In conclusion, this MRD-driven strategy given for a definite period of time leads to a very high rate of uMRD CR in previously untreated CLL fit patients without TP53 aberration and displays an acceptable security profile. To our knowledge, these results are superior to standard FC + rituximab (FCR) or any chemo-free regimen. We hypothesize that this very high rate of bone marrow undetectable MRD will translate in a prolonged PFS while discontinuing treatment. Disclosures Laribi: Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Sandoz: Other: Grant; Roche: Other: Grant; Amgen: Other: Personal fees; Hospira: Other: Grant. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria. Cartron:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cymbalista:Gilead: Honoraria; AbbVie, Inc: Honoraria; Janssen: Honoraria; Sunesis: Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Gorgun, Gullu, Elisabetta Calabrese, Teru Hideshima, Hiroshi Ikeda, Giulia Perrone, Loredana Santo, Diana Cirstea, Paul G. Richardson, and Kenneth C. Anderson. "Immunomodulatory Effects of Lenalidomide and Bortezomib on Bone Marrow Stroma Cell and CD4 T Cell Interaction in Multiple Myeloma." Blood 112, no. 11 (November 16, 2008): 1690. http://dx.doi.org/10.1182/blood.v112.11.1690.1690.
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Abstract The bone marrow (BM) environment consists of extracellular matrix molecules and the cellular compartment including immune cells. Interaction between multiple myeloma (MM) cells, BM cells, and BM-derived soluble factors (BMSF), particularly cytokines, induces growth, survival, migration and drug resistance in MM cells. Even though MM cell interaction with bone marrow stroma cells (BMSC) has been extensively studied, the role of immune cells in the MM bone marrow milieu is not yet defined. Current novel therapies in MM include immunomodulatory agents Lenalidomide (Len) and Bortezomib (Bor). We and others have shown that Bor may mediate anti-MM activity by inhibiting IL-6 production in BMSC, and Len requires CD28 costimulatory signaling to induce T cell proliferation. Here we examined the in vitro immunomodulatory effects of Len and Bor, either alone or in combination, on interaction of CD4 T cells (Th) with BMSF or BMSC in MM. Peripheral blood mononuclear cells (PBMC) were obtained from patients with rel/ref MM or healthy donors and cocultured with allogeneic BMSC or BMSF, in the absence or presence of Len (1uM) for 24–48h and Bor (0.5uM) for the last 2–5 hours. To determine whether Len and Bor regulate cytokine signaling in Th cells, we used flow cytometry to analyse their effects on suppressor of cytokine signaling proteins (SOCS), including intracytoplasmic SOCS1, SOCS2, SOCS3 and CIS expression in Th cells from both healthy donors and patients with MM. Coculture of MM cell lines, including MM1S, MM1R, U266, OPM1, OPM2, RPMI, LR5 and DOX40, with healthy PBMCs induced SOCS3 expression in Th cells; conversely treatment with Len and Bor, alone or in combination, downregulated the SOCS3 expression in Th cells. In the presence of BMSF, SOCS3 expression in Th cells was decreased by treatment with Len alone or in combination with Bor, while Bor alone induced SOCS3 expression. In the cocultures of BMSC and PBMCs, Len and Bor alone induced SOCS3 expression, whereas treatment with Len and Bor combination decreased SOCS3 expression in Th cells. It has been shown that SOCS3 regulates Th cell differentiation and cytokine responses including IL-6R signaling and production of IL-2, IL-10, IFNγ, as well as Th cell differentiation to T-bet expressing Th1 cells. We observed that Len and Bor alone induced IFNγ expression, whereas the combination significantly decreased expression of IFNγ as well as T-bet in Th cells in the BMSC and PBMC coculture. To assess effects of Len and Bor on immune cell proliferation in the BM milieu, healthy or MM-PBMCs were prelabeled with CFSE and cocultured with BMSF or BMSC for 4 days. The proliferation of CD4 T cells and CD8 T cells, B cells and NK cells was assessed by CFSE flow cytometry analysis. Len and Bor induced only Th cell proliferation in the presence of BMSF; however, there was increased proliferation of effector cells including CD4 T cells, CD8 T cells, and NK cells, in the presence of BMSC. Moreover, Len and Bor induced associated changes in the expression of costimulatory molecules including CD28, ICOS, CD274 (PDL1), CD275 (ICOSL), CD276 (B7-H3) on immune cells in the cocultures with BMSF or BMSC. These data demonstrate that modulation of SOCS3 by blocking BMSC derived inhibitory cytokine signaling may enhance effector cells and CD4 T cell response in MM. Ongoing analysis of Lenalidomide and Bortezomib effects on immune cells in the BM environment will both define their role in disease pathogenesis and suggest novel immune-based targeted therapies.
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Zhang, Hongyu, Jia Feng, Wenli Zhang, Qi Chen, Yuanzhen Cao, Kevin Pinz, Fang Liu, Yu Ma, Masayuki Wada, and Yupo Ma. "First-in-Human CD4 CAR Clinical Trial on Peripheral T-Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2881. http://dx.doi.org/10.1182/blood-2019-122789.
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Background CD19 CAR T cell therapy has achieved success in treating acute lymphoblastic leukemia. However, the treatment for Sezary syndrome, an aggressive form of cutaneous peripheral T cell lymphoma (PTCL) has remained a challenge. Despite patients with Sezary syndrome typically receiving multiple treatments within their disease progression, the prognosis is poor with 5 year survival rate of only 24%. Therefore, it is crucial to establish a novel treatment for PTCLs. CD4 is uniformly expressed on most mature T cell lymphoma, which makes it a promising target for treating PTCLs. Here, we present the efficacy of CD4 CAR T cell in our preclinical study and the success in level 1 dose escalation clinical trial on patients with Sezary syndrome. Methods We engineered a CD4 CAR with scFv (single-chain variable fragment) with CD28 and 4-1BB co-activators fused to CD3zeta and a leader sequence of CD8. The efficacy of CD4 CAR was tested with CD4+ leukemic cell line, primary CD4+ PTCL patient samples and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with PTCLs were enrolled in our phase 1 dose escalation trial to evaluate the safety and efficacy of CD4 CAR T cell antitumor activity. Results Coculture assays results showed that CD4 CAR T cells displayed profound tumor killing effects in leukemia cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that CD4 CAR T cells is an effective approach in treating PTCLs. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to CD4 CAR T cells treatment. Noticeably, a 54-yr-old patient diagnosed with Sezary syndrome had achieved complete remission with CD4 CAR T cell therapy. Prior to admission, he had been having symptoms of erythroderma, pruritus and scaling of the skin for over 10 years and had been resistant to multiple lines of chemotherapy. Before the initiation of CAR therapy, patient's body skin has extensive leukemia infiltrate (Fig. 1A) confirmed with skin biopsy (Fig. 1B) with bone marrow and blood comprising 50% leukemic cells (Fig. 1C). Patient received a total dose of 3x10^6 /kg single dose CAR T cells, following which fluconazole and valacyclovir were administrated for infection prophylaxis. Since patient received CD4 CAR T cell infusion, the percentage of CAR T cells (Fig 1. D) in peripheral blood had continue to increase as well as NK cells. (Fig 1. E) On day 13, patient had achieved complete remission with the percentage of leukemia cells in blood decreased to zero (Fig. 1C). On day 28, the appearance of the skin had undergone drastic change from what was before the treatment. Noticeable skin regeneration on both legs of the patients was observed (Fig 1. F). Flow cytometry of bone marrow and peripheral blood confirmed the absence of tumor cells. In addition, Skin biopsy on multiple sites demonstrated absence of leukemia infiltrates post CAR treatment (Fig. 1G). Patient was subsequently discharged with no additional medication needed. Throughout the treatment, patient had developed no infections with Grade II CRS toxicity noted. No other toxicities were observed. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of CD4 CAR T cell therapy in treating patients with refractory Sezary syndrome. cCAR is able to eradicate leukemia blasts, exerting a profound tumor killing effect that is superior to traditional chemotherapies. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Consultancy, Equity Ownership, Research Funding; iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.
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Liu, Fang, Yuanzhen Cao, Kevin Pinz, Yu Ma, Masayuki Wada, Kevin Chen, Gina Ma, et al. "First-in-Human CLL1-CD33 Compound CAR T Cell Therapy Induces Complete Remission in Patients with Refractory Acute Myeloid Leukemia: Update on Phase 1 Clinical Trial." Blood 132, Supplement 1 (November 29, 2018): 901. http://dx.doi.org/10.1182/blood-2018-99-110579.
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Abstract Background CD19-specific chimeric antigen receptor (CAR) T cell therapy has achieved high efficacy in acute lymphoblastic leukemia patients. However, the treatment of acute myeloid leukemia (AML) has remained a particular challenge due to the heterogeneity of AML bearing cells, which renders single antigen targeting CAR T cell therapy ineffective. CLL1 and CD33 are often used as targets for AML CAR T cell therapy. CLL1 is associated with leukemia stem cells and disease relapse, and CD33 is expressed on the bulk AML disease. Previously, we demonstrated the profound anti-tumor activity of CLL1-CD33 compound CAR (cCAR) T cells. Here we present the efficacy of cCAR in preclinical study and update the success in level 1 dose escalation clinical trial on relapsed/refractory AML patients. Methods We engineered a cCAR comprising of an anti-CLL1 CAR linked to an anti- CD33 CAR via a self-cleaving P2A peptide and expressing both functional CAR molecules on the surface of a T-cell cell. We tested the anti-leukemic activities of CLL1-CD33 cCAR using multiple AML cell lines, primary human AML samples, human leukemia cell line (REH cells) expressing either CLL1 or CD33, and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with relapsed/refractory AML were enrolled in our phase 1 dose escalation trial with primary objective to evaluate the safety of cCAR and secondary objective to assess the efficacy of cCAR anti-tumor activity. Results Co-culture assays results showed that cCAR displayed profound tumor killing effects in AML cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that cCAR, targeting two discrete AML antigens: CLL1 and CD33, is an effective two-pronged approach in treating bulk AML disease and eradicating leukemia stem cells. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to cCAR treatment. Noticeably, a 6-yr-old female patient diagnosed with a complex karyotype AML including FLT3-ITD mutation had achieved complete remission. The patient was diagnosed with Fanconi anemia, which had progressed to juvenile myelomonocytic leukemia and eventually transformed into AML. The patient had been resistant to multiple lines of treatments, including 5 cycles of chemotherapy with FLT3 inhibitor prior to receiving cCAR. Before the treatment, patient's leukemia blasts comprised 73% of the peripheral blood mononuclear cells and 81% of the bone marrow. Patient underwent lymphodepletion therapy (Fludarabine and Cyclophosphamide) prior to cCAR infusion. Two split doses, each consisting of 1x106/kg CAR T cells, were infused on day 1 and day 2 respectively. On day 12, while leukemia blast still counting up to 98% of the bone marrow (Fig. 1A), robust CAR T cell expansion was detected in both peripheral blood and bone marrow. On day 19, patient achieved MRD- complete remission with bone marrow aspirates revealing complete ablation of myeloid cells (Fig. 1B). Flow cytometry confirmed the absence of leukemia blasts and showed that CAR T cells comprised 36% of the PBMC and 60% of the bone marrow. The patient later underwent non-myeloablative hematopoietic cell transplantation with less toxicities compared to conventional total body radiation and high dose chemotherapies. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total body radiation or high dose chemotherapies. In addition to AML, cCAR also has the potential to treat blast crisis developed from myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloproliferative neoplasm. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Chen:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC, iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.
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"Increased B-cell ICOSL Expression Improves Chemotherapy Response." Cancer Discovery 10, no. 5 (March 13, 2020): OF8. http://dx.doi.org/10.1158/2159-8290.cd-rw2020-039.
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Angulo, Guillem, Jelena Zeleznjak, Pablo Martínez-Vicente, Joan Puñet-Ortiz, Hartmut Hengel, Martin Messerle, Annette Oxenius, et al. "Cytomegalovirus restricts ICOSL expression on antigen-presenting cells disabling T cell co-stimulation and contributing to immune evasion." eLife 10 (January 18, 2021). http://dx.doi.org/10.7554/elife.59350.
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Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen-presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and limits virus control during the acute MCMV infection. Additionally, we report that blockade of ICOSL in MCMV-infected mice critically regulates the production of MCMV-specific antibodies due to a reduction of T follicular helper and GC B cells. Altogether, these findings reveal a novel mechanism evolved by MCMV to counteract adaptive immune surveillance, and demonstrates a role of the ICOS:ICOSL axis in the host defense against herpesviruses.
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Burbage, Marianne, Francesca Gasparrini, Shweta Aggarwal, Mauro Gaya, Johan Arnold, Usha Nair, Michael Way, Andreas Bruckbauer, and Facundo D. Batista. "Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity." eLife 7 (January 16, 2018). http://dx.doi.org/10.7554/elife.26556.
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Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.
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Deist, Melissa S., Rodrigo A. Gallardo, David A. Bunn, Terra R. Kelly, Jack C. M. Dekkers, Huaijun Zhou, and Susan J. Lamont. "Novel Mechanisms Revealed in the Trachea Transcriptome of Resistant and Susceptible Chicken Lines following Infection with Newcastle Disease Virus." Clinical and Vaccine Immunology 24, no. 5 (March 22, 2017). http://dx.doi.org/10.1128/cvi.00027-17.
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ABSTRACT Newcastle disease virus (NDV) has a devastating impact on poultry production in developing countries. This study examined the transcriptome of tracheal epithelial cells from two inbred chicken lines that differ in NDV susceptibility after challenge with a high-titer inoculum of lentogenic NDV. The Fayoumi line had a significantly lower NDV load postchallenge than the Leghorn line, demonstrating the Fayoumi line's classification as a relatively NDV-resistant breed. Examination of the trachea transcriptome showed a large increase in immune cell infiltration in the trachea in both lines at all times postinfection. The pathways conserved across lines and at all three time points postinfection included iCOS-iCOSL signaling in T helper cells, NF-κB signaling, the role of nuclear factor of activated T cells in the regulation of the immune response, calcium-induced T lymphocyte apoptosis, phospholipase C signaling, and CD28 signaling in T helper cells. Although shared pathways were seen in the Fayoumi and Leghorn lines, each line showed unique responses as well. The downregulation of collagen and the activation of eukaryotic translation initiation factor 2 signaling in the Fayoumis relative to the Leghorns at 2 days postinfection may contribute to the resistance phenotype seen in the Fayoumis. This study provides a further understanding of host-pathogen interactions which could improve vaccine efficacy and, in combination with genome-wide association studies, has the potential to advance strategies for breeding chickens with enhanced resistance to NDV.
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Saliba, David G., Pablo F. Céspedes-Donoso, Štefan Bálint, Ewoud B. Compeer, Kseniya Korobchevskaya, Salvatore Valvo, Viveka Mayya, et al. "Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T cells." eLife 8 (August 30, 2019). http://dx.doi.org/10.7554/elife.47528.
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Planar supported lipid bilayers (PSLB) presenting T cell receptor (TCR) ligands and ICAM-1 induce budding of extracellular microvesicles enriched in functional TCR, defined here as synaptic ectosomes (SE), from helper T cells. SE bind peptide-MHC directly exporting TCR into the synaptic cleft, but incorporation of other effectors is unknown. Here, we utilized bead supported lipid bilayers (BSLB) to capture SE from single immunological synapses (IS), determined SE composition by immunofluorescence flow cytometry and enriched SE for proteomic analysis by particle sorting. We demonstrate selective enrichment of CD40L and ICOS in SE in response to addition of CD40 and ICOSL, respectively, to SLB presenting TCR ligands and ICAM-1. SE are enriched in tetraspanins, BST-2, TCR signaling and ESCRT proteins. Super-resolution microscopy demonstrated that CD40L is present in microclusters within CD81 defined SE that are spatially segregated from TCR/ICOS/BST-2. CD40L+ SE retain the capacity to induce dendritic cell maturation and cytokine production.
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Talaev, V. Yu, O. N. Babaikina, M. V. Talaeva, E. V. Voronina, and I. E. Zaichenko. "EFFECT OF MEASLES VACCINE ON MATURATION OF HUMAN DENDRITIC CELLS IN VITRO." ЗДОРОВЬЕ НАСЕЛЕНИЯ И СРЕДА ОБИТАНИЯ - ЗНиСО / PUBLIC HEALTH AND LIFE ENVIRONMENT, August 2019, 61–66. http://dx.doi.org/10.35627/2219-5238/2019-317-8-61-66.
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The most important means of measles control is live measles vaccine, the high epidemiological effectiveness of which is confirmed by half a century of its use. There is a question of the need to further improve the effectiveness of vaccine prophylaxis, in particular, by increasing the immunogenicity of the used vaccine given the increase in the morbidity of measles in recent years. Investigation of effect features of existing vaccine variants is necessary to identify possible ways to increase their immunogenicity. We investigated the effect of measles culture live vaccine on the maturation of human dendritic cells – the most specialized antigen-presenting cells involved in the induction of an immune response. In vitro incubation of monocytic derived immature dendritic cells with the vaccine initiates the process of their partial maturation, which is manifested in an increase in the number of cells carrying molecules CD86, CD83 and ICOSL (CD275).At the same time they have a reduced expression level of the HLA-DR molecule and chemokine receptors CCR7 and CXCR5 involved in the migration of dendritic cells to peripheral lymphoid organs. In our opinion, the relative weak side of measles vaccine effect on dendritic cell maturation is a factor limiting the immunogenicity of the vaccine, which must be taken into account when developing new measles vaccines.
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Xie, Shihao, Haixia Wei, Anping Peng, Anqi Xie, Jiajie Li, Chao Fang, Feihu Shi, et al. "Ikzf2 Regulates the Development of ICOS+ Th Cells to Mediate Immune Response in the Spleen of S. japonicum-Infected C57BL/6 Mice." Frontiers in Immunology 12 (August 12, 2021). http://dx.doi.org/10.3389/fimmu.2021.687919.
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BackgroundTh cells (helper T cells) have multiple functions in Schistosoma japonicum (S. japonicum) infection. Inducible co-stimulator (ICOS) is induced and expressed in activated T lymphocytes, which enhances the development of B cells and antibody production through the ICOS/ICOSL pathway. It remains unclear about the role and possible regulating mechanism of ICOS+ Th cells in the spleen of S. japonicum-infected C57BL/6 mice.MethodsC57BL/6 mice were infected with cercariae of S. japonicum through the abdomen. The expression of ICOS, activation markers, and the cytokine production on CD4+ ICOS+ Th cells were detected by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Moreover, the differentially expressed gene data of ICOS+ and ICOS− Th cells from the spleen of infected mice were obtained by mRNA sequencing. Besides, Western blot and chromatin immunoprecipitation (ChIP) were used to explore the role of Ikzf2 on ICOS expression.ResultsAfter S. japonicum infection, the expression of ICOS molecules gradually increased in splenic lymphocytes, especially in Th cells (P < 0.01). Compared with ICOS− Th cells, more ICOS+ Th cells expressed CD69, CD25, CXCR5, and CD40L (P < 0.05), while less of them expressed CD62L (P < 0.05). Also, ICOS+ Th cells expressed more cytokines, such as IFN-γ, IL-4, IL-10, IL-2, and IL-21 (P < 0.05). RNA sequencing results showed that many transcription factors were increased significantly in ICOS+ Th cells, especially Ikzf2 (P < 0.05). And then, the expression of Ikzf2 was verified to be significantly increased and mainly located in the nuclear of ICOS+ Th cells. Finally, ChIP experiments and dual-luciferase reporter assay confirmed that Ikzf2 could directly bind to the ICOS promoter in Th cells.ConclusionIn this study, ICOS+ Th cells were found to play an important role in S. japonicum infection to induce immune response in the spleen of C57BL/6 mice. Additionally, Ikzf2 was found to be one important transcription factor that could regulate the expression of ICOS in the spleen of S. japonicum-infected C57BL/6 mice.
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Michallet, Anne-Sophie, Rémi Letestu, Magali Le Garff-Tavernier, Carmen Mariana Aanei, Michel Ticchioni, Marie-Sarah Dilhuydy, Fabien Subtil, et al. "A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial." Blood, November 9, 2020. http://dx.doi.org/10.1182/blood.2020008164.
Full textAbstract:
Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL-07 FILO; NCT02666898) in previously untreated, medically-fit patients (N=135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N=130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n=10) received ibrutinib for 6 additional months, while those in partial remission and/or with BM MRD ≥0.01% - the majority (n=120) - also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed 3 monthly and peripheral blood MRD 6 monthly. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0 to 99.5) and 98% (95.1 to 100), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically-fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity.
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Imredy, John P., Bharathi Balasubramanian, Edward V. Lis, Armando Lagrutta, and Frederick Sannajust. "Abstract 95: Pharmacological Characterization of Adenosine Effects on Spontaneously Beating Human-IPSC-Derived Cardiomyocytes." Circulation Research 117, suppl_1 (July 17, 2015). http://dx.doi.org/10.1161/res.117.suppl_1.95.
Full textAbstract:
Purified human-Induced Pluripotent Stem Cell-derived cardiomyocytes (hIPSC-CMs: iCells®, Cellular Dynamics) form electrically coupled, spontaneously beating cell monolayers (syncytia) upon plating and continuous culture. In this study, we investigate the pharmacology of the hIPSC-CM adenosine (ADO) response via the use of selective A1 and A2A-receptor antagonists and equilibrative nucleoside transporter type-1 (ENT1) inhibitors. After a 14-day culture in 96-well impedance electrode-plates (ACEA Biosciences), the spontaneous iCell beating rates are highly stable from well to well, with a mean beat period of 1.7 sec at 37°C, and a coefficient of variation (CV) < 1% . Extracellularly applied ADO inhibits the spontaneous beating rate of iCells with an IC 50 = 2.2 μM, and a saturation value of near 50% inhibition. ADO also destabilizes the beat period (CV EC 50 = 1.2 μM) with a maximum CV of 20% at saturating ADO concentrations. The ADO IC 50 is shifted to 248 μM upon pre-incubation of the iCells with 1 μM of an A1-selective antagonist DPCPX (A1 K i =3.9 nM), but not the A2A-selective antagonist ZM241385 (A2A K i =1nM). The duration of the depressive effect of ADO on beating rate is transient, even at super-saturating ADO concentrations, and depends on the well ADO concentration. The ENT1 inhibitor Draflazine (ENT1 pK i =9.5) pre-applied at 0.1 μM increases ADO sensitivity by 4-fold one hour after ADO application. Moreover, at any given ADO concentration, the duration of beating rate depression can be prolonged in a concentration-dependent manner by ENT1 inhibitors, with the prolongation-response curve nearly matching the ENT1 IC 50 s for tested ENT1 inhibitors (Draflazine, NBTI, Dilazep, and Dipyridamole). These findings suggest that the pool of ADO in the test well is cleared by uptake via endogenous ENT1 and support the role of equilibrative ADO uptake in limiting the duration of action of ADO on A1 receptors in cardiomyocytes. We are extending our investigation to the downstream target of A1 receptor activity, and the putative role of IK ACH/ADO as the underlying mechanism of beat rate slowing and irregularity. In conclusion, the hIPSC-CM model provides a useful model for investigation of ADO pharmacology of the heart.
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Shimizu, Koichi, Peter Libby, Viviane Z. Rocha, Eduardo J. Folco, Rica Shubiki, Kevin J. Croce, Nancy Hogg, Richard N. Mitchell, and Daniel I. Simon. "Abstract 3689: Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_467-a.
Full textAbstract:
Background: The S100 calcium-binding proteins MRP-8 (S100A8) and MRP-14 (S100A9) heterodimerize to form MRP-8/14 complexes that regulate myeloid cell function, control inflammatory responses, and serve as an early serum marker for monitoring acute allograft rejection. Despite functioning as a putative pro-inflammatory mediator, the pathophysiological role of MRP-8/14 in cardiovascular disease remains unknown. This study used murine cardiac transplantation to investigate the role of MRP-14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14−/−) lacking MRP-8/14 complexes. Results: In major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor hearts and C57BL/6 recipients), allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14−/ −recipients compared to > 12 weeks (n = 15, p<0.0001) in wild-type (WT) recipients. At 2 week post-transplantation, allografts in MRP14−/ − recipients had significantly higher parenchymal rejection (PR) scores (2.8 ± 0.8, n=8) than WT recipients (0.8 ± 0.8, n=12, p<0.0001). MRP14−/ − recipients had significantly increased allograft accumulation of T cells and macrophages and mRNA levels of IFN-γ and IFN-γ–associated chemokines (IP-10, Mig, and I-TAC) compared to WT recipients. The MRP14−/− recipients also had significantly more lymphocytes in draining lymph nodes than WT recipients (cell number per lymph nodes: 23.7 ± 0.7 x 105 for MRP14−/− vs. 6.0 ± 0.2 x 105 for WT, p < 0.0001). MRP14−/− dendritic cells (DC) stimulated with IFN-γ expressed significantly higher levels of the co-stimulatory molecules CD86 and ICOSL, and mixed leukocyte reaction using allo-EC-primed MRP14−/− DC resulted in significantly higher antigen-presenting function than WT DC. Conclusion: Taken together, these observations indicate that MRP-8/14 complexes participate in acute allograft rejection by modulating dendritic cell antigen presentation and T cell priming. The unexpected finding that deficiency of MRP-8/14 complexes exacerbates acute allograft rejection indicates that MRP-8/14 has distinct roles in modulating immune cell functions, such as migration and antigen presentation. This research has received full or partial funding support from the American Heart Association, AHA National Center.